The multidrug resistance/ATP-binding cassette (MDR/ABC) superfamily in humans includes genes whose products represent membrane proteins involved in energy-dependent transport of a wide variety of substrates across a membrane (see, e.g., Dean, M. and Allikmets, R. (1995) Curr. Opin. Genet. Dev. 5, 79–785). The overexpression of ABC transporters has been linked with drug resistance since the 1976 discovery of P-glycoprotein and the subsequent cloning of the encoding gene, MDR-1. Resistance ensues from reduced intracellular drug concentrations, a result of active drug efflux. The subsequent identification of the multidrug resistance associated protein (MRP), encoded by the MRP gene, heralded a new era that recognized the complexity of the problem and catalyzed the search for additional transporters. MDR-1 and MRP are members of the expanding superfamily of ATP-binding cassette proteins (ABC proteins). This superfamily is comprised of a large and diverse group of proteins that transport solutes across biological membranes. Transmembrane domains are thought to form a pathway through which substrates cross cell membranes, while two ATP-binding domains hydrolyze ATP to accomplish substrate transport. Mutations in ABC transporters have been identified as etiologic in diseases including hyperinsulinemic hypoglycemia of infancy, adrenoleukodystrophy, and cystic fibrosis. The transporters MDR-1 and MRP, and possibly the multispecific organic anion transporter, cMOAT, are thought to be involved in both normal excretion of xenobiotics and in drug resistance. The ABC superfamily also includes a number of transporters without known function and the potential exists to identify additional transporters which mediate drug resistance.
Recent studies have described a number of cell lines with resistance to mitoxantrone that exhibit multidrug resistance without overexpression of MRP. In addition to mitoxantrone, these cell lines are particularly resistant to anthracyclines, and a have an energy-dependent reduction in the accumulation of daunomycin and mitoxantrone. Cell lines possessing this phenotype include sublines derived by selection of leukemic cells, as well as breast, colon, and gastric carcinomas.